WO1999045987A1 - Powder inhaler - Google Patents

Powder inhaler Download PDF

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Publication number
WO1999045987A1
WO1999045987A1 PCT/EP1999/001487 EP9901487W WO9945987A1 WO 1999045987 A1 WO1999045987 A1 WO 1999045987A1 EP 9901487 W EP9901487 W EP 9901487W WO 9945987 A1 WO9945987 A1 WO 9945987A1
Authority
WO
WIPO (PCT)
Prior art keywords
capsule
coating
polymer
piercing means
inhaler
Prior art date
Application number
PCT/EP1999/001487
Other languages
French (fr)
Inventor
Claude Moulin
Original Assignee
Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft Mbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to DE29923581U priority Critical patent/DE29923581U1/en
Priority to BR9908587-9A priority patent/BR9908587A/en
Priority to EP99911753A priority patent/EP1061979B1/en
Priority to CA002322575A priority patent/CA2322575C/en
Priority to IL13812199A priority patent/IL138121A/en
Priority to DE69922175T priority patent/DE69922175T2/en
Priority to AU30323/99A priority patent/AU750844B2/en
Priority to PL99342825A priority patent/PL187578B1/en
Application filed by Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft Mbh filed Critical Novartis Ag
Priority to NZ506645A priority patent/NZ506645A/en
Priority to AT99911753T priority patent/ATE283083T1/en
Priority to JP2000535398A priority patent/JP4082864B2/en
Publication of WO1999045987A1 publication Critical patent/WO1999045987A1/en
Priority to US09/657,967 priority patent/US6488027B1/en
Priority to HK01104311A priority patent/HK1035151A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0028—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/003—Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using capsules, e.g. to be perforated or broken-up
    • A61M15/0033—Details of the piercing or cutting means
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/06—Solids
    • A61M2202/064—Powder

Definitions

  • This invention relates to single dose dry powder inhalers in which medicament is stored in a capsule prior to release.
  • Capsule-cutting means are disclosed for example in DE 39 27 170 and in EP 528 764.
  • Inhaler A An inhaler for powdered medicaments is described in US patent 3,991 ,761 (hereafter referred to as Inhaler A).
  • Inhaler A comprises a recess for receiving a capsule, and push buttons are provided which carry sharpened metal pins and are held in position by biasing springs. In use the capsule is pierced by the spring-loaded pins and on release of the push buttons, the pins retract from the perforated capsule allowing medicament to pass out therefrom.
  • a problem encountered with known capsule-piercing mechanisms is that the cutting means, e.g. metal pin, can become adhered to a capsule wall. This prevents complete release of medicament for inhalation and causes frustration amongst users.
  • the cutting means e.g. metal pin
  • this invention provides an inhaler comprising metal capsule- piercing means which is coated with a polymer.
  • this invention provides the use of polymer-coated metal capsule- piercing means in an inhaler for faster, more complete and effective release of a medicament.
  • piercing means may have at least one coating of an inert polymer characterized by (i) excellent antiadhesive properties, i.e. highly lubricating, properties, for example a polymer having a low friction coefficient, e.g. a friction coefficient (which is defined as the dimensionless quotient obtained by dividing the value of the force necessary to move one body over another at a constant speed by the weight of the body) of at least 0.1 under light loads and (ii) high thermal and chemical inertness.
  • an inert polymer characterized by (i) excellent antiadhesive properties, i.e. highly lubricating, properties, for example a polymer having a low friction coefficient, e.g. a friction coefficient (which is defined as the dimensionless quotient obtained by dividing the value of the force necessary to move one body over another at a constant speed by the weight of the body) of at least 0.1 under light loads and (ii) high thermal and chemical inertness.
  • Preferred polymers include any inert polymer, for example fluorocarbon polymers containing -CF 2 -CF 2 - units, including copolymers thereof, having different terminal groups at the polymer chain ends, for example hydrogen, a halogen, a halogenated carbon, e.g. trichlorocarbon, a carboxylic acid, an alkylgroup, or an alcohol, depending on the method of producing the polymer.
  • a halogen e.g. trichlorocarbon
  • carboxylic acid e.g. trichlorocarbon
  • carboxylic acid e.g. trichlorocarbon
  • an alkylgroup e.g. trichlorocarbon
  • TEFLON ® polytetrafluoroethylene
  • the molecular weights of the polymers used for coating the piercing means may range from about 2x10 3 to about 2x10 6 Daltons.
  • these polymers are incorporated homogeneously, e.g.
  • alloys may contain chromium and/or one or more elements of Group VIII of the Periodic Table, for example iron, cobalt, nickel, preferably nickel, and/or a noble metal, for example ruthenium, rhodium, palladium.
  • nickel phosphorous alloys which preferably contain about 90 to 93 % by weight nickel and about 7 to 10 % by weight phosphorous.
  • Coterminous piercing of the capsule may be achieved by one or more pins at each end of the capsule.
  • the coating or coatings may cover at least the portion of a pin or pins which come in contact and pierce the capsule, but preferably they cover the whole surface of the pin or pins. More than one alloy may be used to apply more than one coating to the pins, particularly preferred are two coatings.
  • the polymer coating or coatings may typically have a total thickness of between about 1 to about 30 microns, for example a first coating may have a thickness of about 5 to about 15 microns, and a second coating may have a thickness of about 3 to 10 microns.
  • piercing means may be coated with PTFE or an alloy matrix, e.g. a chromium or a nickel phosphorous alloy, or an alloy matrix containing PTFE particles, e.g. a PTFE-containing nickel phosphorous alloy, also known as CHENIFLON TM .
  • steel pins e.g. stainless steel pins, for use in an inhalation device are coated with a first layer of a nickel phosphorous alloy, e.g.
  • NIPLOY TM to a thickness of between about 5 and about 15 microns and a second layer containing about 20 to 30 % by volume PTFE particles homogeneously incorporated in a nickel phosphorous alloy matrix may be applied at a thickness of between 3 and 10 microns onto the first layer.
  • the composition of a plated deposit contains about 80 to 95 %, e.g. 85 % by weight nickel, 5 to 20 %, e.g. 6.6 % by weight phosphorous and up to 30 %, e.g. 8.4 % by weight PTFE.
  • the PTFE content in a composite of 8.4 % by weight may correspond to approximately 25 % by volume in the deposit.
  • Polymers may be applied to the pins, e.g. steel pins, using techniques suitable to give a uniform coating.
  • conventional coating techniques include (i) applying the polymers in form of a, preferably fine, dispersion and (ii) evaporating the liquid medium to form the coating.
  • Such techniques include for example
  • Suitable liquid media to form a dispersion include aqueous solutions, freons, for example dichlorodifluoromethane, dichlorotetrafluoroethane, and the like, including mixtures of these media.
  • the dispersion may be preferably fine such that the particles remain uniformly distributed through the solution with little or no agitation.
  • the polymer coatings are formed by depositing a coating using plating processes, particularly preferred is an electroless nickel composite coating process.
  • a corresponding composite process further includes particles in the plating solution, for example polymers, e.g. PTFE.
  • a chemical composition of a plating solution may contain 6 g/l nickel metal, 30 g/l sodium hypophosphite, 3-6 g/l PTFE powder, 10-30 g/l organic acids, and stabilizers in picomolar concentrations.
  • Typical operating conditions may include a pH of about 4.7 to 5.0 and a temperature of about 183 to 193 F.
  • a coating may be applied by electroless nickel plating or composite coating, e.g. using the Cheniflon TM process from the Argos company of Italy.

Abstract

This invention relates to single dose dry powder inhalers in which medicament is stored in a capsule and is released by piercing the capsule wall with polymer-coated steel pins. Methods of preparation of polymer-coated piercing means and their use in releasing the medicament from the capsule are described.

Description

POWDER INHALER
This invention relates to single dose dry powder inhalers in which medicament is stored in a capsule prior to release.
It is well-known to pierce capsules with a metal pin or other cutting means in an inhaler. Capsule-cutting means are disclosed for example in DE 39 27 170 and in EP 528 764.
An inhaler for powdered medicaments is described in US patent 3,991 ,761 (hereafter referred to as Inhaler A). Inhaler A comprises a recess for receiving a capsule, and push buttons are provided which carry sharpened metal pins and are held in position by biasing springs. In use the capsule is pierced by the spring-loaded pins and on release of the push buttons, the pins retract from the perforated capsule allowing medicament to pass out therefrom.
A problem encountered with known capsule-piercing mechanisms is that the cutting means, e.g. metal pin, can become adhered to a capsule wall. This prevents complete release of medicament for inhalation and causes frustration amongst users.
The present applicants have sought to overcome this problem, and have found that a polymer coating applied to the metal pins permits complete release after capsule- puncture.
In one aspect, therefore, this invention provides an inhaler comprising metal capsule- piercing means which is coated with a polymer.
In another aspect this invention provides the use of polymer-coated metal capsule- piercing means in an inhaler for faster, more complete and effective release of a medicament.
In accordance with the present invention, piercing means are provided that may have at least one coating of an inert polymer characterized by (i) excellent antiadhesive properties, i.e. highly lubricating, properties, for example a polymer having a low friction coefficient, e.g. a friction coefficient (which is defined as the dimensionless quotient obtained by dividing the value of the force necessary to move one body over another at a constant speed by the weight of the body) of at least 0.1 under light loads and (ii) high thermal and chemical inertness. Preferred polymers include any inert polymer, for example fluorocarbon polymers containing -CF2-CF2- units, including copolymers thereof, having different terminal groups at the polymer chain ends, for example hydrogen, a halogen, a halogenated carbon, e.g. trichlorocarbon, a carboxylic acid, an alkylgroup, or an alcohol, depending on the method of producing the polymer. Especially preferred is polytetrafluoroethylene (PTFE) also known as TEFLON®. The molecular weights of the polymers used for coating the piercing means may range from about 2x103 to about 2x106 Daltons. Preferably, these polymers are incorporated homogeneously, e.g. uniformly distributed, for example in an alloy matrix, at a concentration of up to 30 %, e.g. from 5 to 30 %. These alloys may contain chromium and/or one or more elements of Group VIII of the Periodic Table, for example iron, cobalt, nickel, preferably nickel, and/or a noble metal, for example ruthenium, rhodium, palladium. Particularly preferred are nickel phosphorous alloys which preferably contain about 90 to 93 % by weight nickel and about 7 to 10 % by weight phosphorous.
Coterminous piercing of the capsule may be achieved by one or more pins at each end of the capsule. The coating or coatings may cover at least the portion of a pin or pins which come in contact and pierce the capsule, but preferably they cover the whole surface of the pin or pins. More than one alloy may be used to apply more than one coating to the pins, particularly preferred are two coatings. The polymer coating or coatings may typically have a total thickness of between about 1 to about 30 microns, for example a first coating may have a thickness of about 5 to about 15 microns, and a second coating may have a thickness of about 3 to 10 microns.
Thus, in one embodiment of this invention, piercing means may be coated with PTFE or an alloy matrix, e.g. a chromium or a nickel phosphorous alloy, or an alloy matrix containing PTFE particles, e.g. a PTFE-containing nickel phosphorous alloy, also known as CHENIFLON™. In a particularly preferred embodiment of this invention, steel pins, e.g. stainless steel pins, for use in an inhalation device are coated with a first layer of a nickel phosphorous alloy, e.g. NIPLOY™, to a thickness of between about 5 and about 15 microns and a second layer containing about 20 to 30 % by volume PTFE particles homogeneously incorporated in a nickel phosphorous alloy matrix may be applied at a thickness of between 3 and 10 microns onto the first layer.
Preferably, the composition of a plated deposit contains about 80 to 95 %, e.g. 85 % by weight nickel, 5 to 20 %, e.g. 6.6 % by weight phosphorous and up to 30 %, e.g. 8.4 % by weight PTFE. The PTFE content in a composite of 8.4 % by weight may correspond to approximately 25 % by volume in the deposit.
Polymers may be applied to the pins, e.g. steel pins, using techniques suitable to give a uniform coating. Typically, conventional coating techniques include (i) applying the polymers in form of a, preferably fine, dispersion and (ii) evaporating the liquid medium to form the coating. Such techniques include for example
(i) dipping the pins into a dispersion of an alloy and controlling the coating thickness by polymer concentration, rate of dipping and withdrawing, and number of applications; (ii) wiping or brushing dilute alloy dispersions onto pin surfaces, particularly useful for partial surface coating; (iii) spraying, for example air spraying of an alloy dispersed in a less volatile solvent using conventional spray equipment, airless spraying using dilute alloy dispersions, or electrostatic spraying; (iv) depositing a coating using aerosol formulations; (v) by ultraviolet photopolymerization; (vi) by RF sputtering; or (vii) by electrophoresis of such a dispersion onto the pins.
Suitable liquid media to form a dispersion include aqueous solutions, freons, for example dichlorodifluoromethane, dichlorotetrafluoroethane, and the like, including mixtures of these media. The dispersion may be preferably fine such that the particles remain uniformly distributed through the solution with little or no agitation. However, most preferably the polymer coatings are formed by depositing a coating using plating processes, particularly preferred is an electroless nickel composite coating process.
Typically, in an electroless nickel plating process direct reduction of the nickel onto the surface takes place in solution in the presence of reducing agents which provide the necessary energy, e.g. sodium hypophosphite, boron compounds or hydrazine. Most preferably the reduction reaction is fueled by hypophosphite, which results in co- deposition of small amounts of phosphorous, e.g. up to 10 %, e.g. from about 7 to 10 % by weight. A corresponding composite process further includes particles in the plating solution, for example polymers, e.g. PTFE. Typically a chemical composition of a plating solution may contain 6 g/l nickel metal, 30 g/l sodium hypophosphite, 3-6 g/l PTFE powder, 10-30 g/l organic acids, and stabilizers in picomolar concentrations. Typical operating conditions may include a pH of about 4.7 to 5.0 and a temperature of about 183 to 193 F.
Thus, in a particularly preferred embodiment a coating may be applied by electroless nickel plating or composite coating, e.g. using the Cheniflon™ process from the Argos company of Italy.
The following non-limiting examples were carried out to illustrate the processes of the present invention:
Test 1.
50 Beclometason 400 Cyclocaps® are used successively in Inhaler A with uncoated steel pins at 20°C. After perforation of each capsule the push buttons are released and it is observed that the pins are retained in, or incompletely withdrawn from, 15 capsules.
This is repeated with inhaler A with Niploy " and Cheniflon™ coated steel pins and no pin retention is observed in any capsule.
Test 2.
50 Salbutanol 200 Cyclocaps® are used successively in Inhaler A with uncoated pins at 20°C. After perforation of each capsule the push buttons are released and the pins are retained in, or incompletely withdrawn from, 18 capsules.
This is repeated with inhaler A with Niploy™ and Cheniflon™ coated pins and no pin retention by any capsule is observed.

Claims

1. Use of polymer-coated metal capsule-piercing means in an inhaler device.
2. Use as claimed in claim 1 wherein the polymer is polytetrafluoroethylene in an alloy matrix.
3. Use as claimed in claim 1 or claim 2 wherein the capsule-piercing means is a sharpened steel pin.
4. An inhaler comprising polymer-coated steel capsule-piercing means.
5. An inhaler according to claim 4 wherein said steel capsule-piercing means are coated with a first coating of a nickel phosphorous alloy and a second coating of a nickel phosphorous alloy containing PTFE particles.
6. An inhaler according to claims 4 or 5 wherein the total thickness of all polymer coating is 5 to 30 microns.
7. Use of electroless nickel composite coating process to coat a PTFE/nickel alloy composite layer onto capsule-piercing means for an inhaler.
8. Coated capsule-piercing means substantially as herein described.
9. A method of preparing polymer-coated piercing means for an inhaler comprising coating the piercing means with a first coating of a nickel phosphorous alloy and a second coating of a nickel phosphorous alloy containing PTFE particles.
PCT/EP1999/001487 1998-03-10 1999-03-08 Powder inhaler WO1999045987A1 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
AU30323/99A AU750844B2 (en) 1998-03-10 1999-03-08 Powder inhaler
EP99911753A EP1061979B1 (en) 1998-03-10 1999-03-08 Powder inhaler
CA002322575A CA2322575C (en) 1998-03-10 1999-03-08 Powder inhaler
IL13812199A IL138121A (en) 1998-03-10 1999-03-08 Powder inhaler
DE69922175T DE69922175T2 (en) 1998-03-10 1999-03-08 powder inhaler
DE29923581U DE29923581U1 (en) 1998-03-10 1999-03-08 Powder inhaler
PL99342825A PL187578B1 (en) 1998-03-10 1999-03-08 Inhaler for podwery substances
BR9908587-9A BR9908587A (en) 1998-03-10 1999-03-08 Dust Inhaler
NZ506645A NZ506645A (en) 1998-03-10 1999-03-08 Inhaler with capsule piercing means comprising polymer-coated steel
AT99911753T ATE283083T1 (en) 1998-03-10 1999-03-08 POWDER INHALER
JP2000535398A JP4082864B2 (en) 1998-03-10 1999-03-08 Powder inhaler
US09/657,967 US6488027B1 (en) 1998-03-10 2000-09-08 Powder inhaler
HK01104311A HK1035151A1 (en) 1998-03-10 2001-06-20 Powder inhaler.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9805102.2 1998-03-10
GBGB9805102.2A GB9805102D0 (en) 1998-03-10 1998-03-10 Device

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US09/657,967 Continuation US6488027B1 (en) 1998-03-10 2000-09-08 Powder inhaler

Publications (1)

Publication Number Publication Date
WO1999045987A1 true WO1999045987A1 (en) 1999-09-16

Family

ID=10828321

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP1999/001486 WO1999045986A1 (en) 1998-03-10 1999-03-08 Powder inhaler
PCT/EP1999/001487 WO1999045987A1 (en) 1998-03-10 1999-03-08 Powder inhaler

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/001486 WO1999045986A1 (en) 1998-03-10 1999-03-08 Powder inhaler

Country Status (19)

Country Link
US (1) US6488027B1 (en)
EP (1) EP1061979B1 (en)
JP (2) JP4082864B2 (en)
KR (1) KR100585483B1 (en)
CN (1) CN1212868C (en)
AT (1) ATE283083T1 (en)
AU (1) AU750844B2 (en)
BR (2) BR9908626A (en)
CA (1) CA2322575C (en)
CO (1) CO5080779A1 (en)
DE (2) DE69922175T2 (en)
ES (1) ES2232119T3 (en)
GB (1) GB9805102D0 (en)
HK (1) HK1035151A1 (en)
IL (1) IL138121A (en)
NZ (1) NZ506645A (en)
PL (1) PL187578B1 (en)
PT (1) PT1061979E (en)
WO (2) WO1999045986A1 (en)

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WO2007116002A1 (en) 2006-04-11 2007-10-18 Boehringer Ingelheim International Gmbh Inhaler
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US9421166B2 (en) 2001-12-19 2016-08-23 Novartis Ag Pulmonary delivery of aminoglycoside
US9554993B2 (en) 1997-09-29 2017-01-31 Novartis Ag Pulmonary delivery particles comprising an active agent
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US10124128B2 (en) 2001-11-14 2018-11-13 Bgp Products Operations Gmbh Aerosolization apparatus with removable mouthpiece
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JP3094437U (en) 2003-06-20
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US6488027B1 (en) 2002-12-03
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KR100585483B1 (en) 2006-06-02
PT1061979E (en) 2005-02-28
HK1035151A1 (en) 2001-11-16
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ATE283083T1 (en) 2004-12-15
CO5080779A1 (en) 2001-09-25

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